How Goals Help to Determine Frontline Treatment in HCC

Michael A. Morse, MD, FACP:One of the challenges with treating hepatocellular carcinoma is not just the cancer, it’s the underlying liver function. In fact, that really dictates often what can be done for people. I’ve often had patients who appear to have disease that could be resectable, but unfortunately they have portal hypertension, and that wouldn’t allow them to have surgery because there’s a high risk of liver failure. They may be Child-Pugh B liver function. Again, there’s a high risk of liver failure if you try to operate on somebody and resect disease with Child-Pugh B. So the liver function also comes into play with later stages. With other cancers we’ve often just looked at TNM [tumor, node, metastasis] staging—the size of the tumor, the multiplicity, whether a lymph node is involved. But for a hepatocellular carcinoma with a more advanced disease, what becomes equally important is are they Child-Pugh A, B, or perhaps C, and what’s their performance status—is it 0 or 1, 2, or worse? All of those reflect both staging but also the therapy they can be offered.

The first question of anybody who has advanced disease is, what are their goals? Are they looking to hit a milestone? Are they just looking for longer survival? Quality of life is obviously important. There may be certain toxicities they’re concerned about. They may have certain comorbidities that may affect whether certain treatments are appropriate. But in a case like this one, where a person has a good performance status, they’re Child-Pugh A, I think it’s very appropriate to offer systemic therapy because we know that the first line and second line have survival benefits associated with therapy.

The FDA-approved first-line therapies are either lenvatinib or sorafenib. Lenvatinib and sorafenib have been compared, of course, in a randomized trial called the REFLECT trial. While lenvatinib was found to be noninferior to sorafenib, it did have a better progression-free survival and also had a higher response rate. In this case, I think it was very appropriate to choose lenvatinib. It also could have been appropriate to choose sorafenib since they’re both FDA approved in the frontline setting.

Many patients, when they come in to see me, have seen immunotherapy on television and they then want to be treated with immunotherapy. They don’t always know what that means, but they know they want it. How do we discuss that with people? Unfortunately, there isn’t an FDA-approved frontline immunotherapy currently. The CheckMate 459 trial, which compared nivolumab with sorafenib, did not meet its endpoint, and so we don’t offer this therapy. Outside of a clinical trial, we don’t offer immunotherapy in the first line.

In characterizing the clinical response in treatment for hepatocellular carcinoma, you can use either RECIST [Response Evaluation Criteria In Solid Tumors] 1.1 or you can use modified RECIST. RECIST 1.1 looks at the longest single dimensions of measurable lesions, and modified RECIST looks at the longest dimensions of vascularized areas or enhancing areas on a CT [computed tomography] scan with contrast. It’s important in analyzing any clinical trial to understand which one was being used in those studies, and when they report the outcomes that you know whether it was RECIST or modified RECIST used. In clinical practice, I think we tend to use modified RECIST because it’s something you can do with your eyes. You don’t have to do precise measurements. You can see the vascularized areas of the tumor are smaller. In this case we’re not actually told whether it was RECIST or modified RECIST, but we’re told this individual had a partial response. In that situation, it’s inevitable that unfortunately there will be progression of disease but initially a very good response.

In terms of the toxicities, I would say they tolerated it as expected. The side effects of the lenvatinib as a VEGF TKI [tyrosine kinase inhibitor] are those of any other VEGF TKIs, so you can have hypertension, which is 1 of its more common adverse effects, but also diarrhea, hand-foot syndrome, fatigue, proteinuria, and there can be cardiovascular events. But I would say this adverse effect profile in this individual is pretty much as expected.

Transcript edited for clarity.

Case: 63-Year-Old Male with R/R mHCC

February 2018: Initial presentation

• A 63-year-old man with chronic HBV infection referred for further imaging studies based on suspicious findings during routine ultrasound for HCC

Initial Clinical Workup

• AFP: 300 IU/mL
• Child-Pugh A
  • Platelets: 210,000 cells/mcL
  • Bilirubin: 1.2 mg/dL
  • Albumin: 3.6 g/dL
  • INR: 1.1
  • No hepatic encephalopathy
  • Ascites not present
• Imaging: CT revealed 2 lesions in right hepatic lobe (2cm, 5cm); no extrahepatic disease; no cirrhosis; no portal hypertension
• BCLC: B
• PS: 0

Treatment

• Patient underwent right hepatectomy; negative margins; no vascular invasion
• AFP: WNL

December 2018

• On routine follow-up, imaging showed new lesion in left hepatic lobe (~2.3cm)
• Chest CT showed 3 small lesions (<1cm) in upper left lobe of lung
• Patient started on lenvatinib 12 mg QD; experienced moderate diarrhea and fatigue
• Imaging at 3 and 6 months showed partial response
• AFP: 100 IU/mL
• BCLC: C
• PS: 0

August 2019

• Routine follow-up blood sample reveals AFP 450 IU/mL
• CT scan showed progression in the lung and 2 new liver lesions; remains Child-Pugh A
• Patient started on cabozantinib 60 mg QD
• Patient developed grade 2 diarrhea; dose-reduction to 40 mg QD
• Imaging at 3 months showed stable disease
• Imaging at 6 months showed partial response